The ribonucleoprotein TDP-43 is an archetypical RNA-binding protein involved in alternative splicing and transcriptional regulation. Under stress conditions, the protein is translocated to the cytoplasm where it forms ‘stress granules’ as membraneless organelles by coacervating with RNA. TDP-43 also undergoes aberrant proteolytic cleavage, the C-terminal fragments of which form cytoplasmic amyloid inclusions that are implicated in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Such inclusions are also observed in increasing number of other neurodegenerative diseases. Interestingly, amyloid inclusions of both TDP-43 and α-synuclein (αS) are also commonly observed to be colocalized in many of these pathologies, raising the possibility of direct interactions and co-aggregation between the two proteins. Our lab set out to investigate this possibility, and we discovered that the prion-like pathogenic C-terminal domain of (TDP-43 PrLD) and αS interact synergistically with one another to augment each other’s aggregation towards hybrid fibrils. PrLD is an aggregation-prone fragment generated both by alternative splicing and aberrant cleavage of full length TDP-43. αS also modulates liquid droplets formed by TDP-43 PrLD and RNA to promote insoluble amyloid aggregates implicating deleterious ramifications on stress granule biology. Importantly, the cross-seeded hybrid aggregates show greater cytotoxicity to the neuronal cells as compared to the individual homotypic aggregates suggesting that the interactions between the two proteins have a discernable impact on cellular functions. The results bring forth insights into TDP-43 – αS interactions that could help explain clinical and pathological presentations in patients with co-morbidities involving the two proteins.

Cross-propagation of TDP-43 and α-Synuclein.

ACS Spring Meeting 2021

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